Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 184
Filtrar
1.
Nat Commun ; 11(1): 319, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949159

RESUMO

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.

2.
Lancet Oncol ; 21(2): 283-293, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31870811

RESUMO

BACKGROUND: Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. METHODS: In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5-24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. FINDINGS: Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22-0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48-0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31-0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40-1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. INTERPRETATION: We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. FUNDING: Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

3.
Ann Surg Oncol ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820212

RESUMO

BACKGROUND: In the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial and the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, matted nodes with gross extracapsular extension (ECE), a risk factor for locoregional recurrence, were an indication for axillary lymph node dissection (ALND), but the effect of microscopic ECE (mECE) in the sentinel lymph nodes (SLNs) on recurrence was not examined. METHODS: Between 2010 and 2017, 811 patients with cT1-2N0 breast cancer and SLN metastasis were prospectively managed according to Z0011 criteria, with ALND for those with more than two positive SLNs or gross ECE. Management of mECE was not specified. In this study, we compare outcomes of patients with one to two positive SLNs with and without mECE, treated with SLN biopsy alone (n = 685). RESULTS: Median patient age was 58 years, and median tumor size was 1.7 cm. mECE was identified in 210 (31%) patients. Patients with mECE were older, had larger tumors, and were more likely to be hormone receptor positive and HER2 negative, have two positive SLNs, and receive nodal radiation. At a median follow-up of 41 months, no isolated axillary failures were observed. There were 11 nodal recurrences; two supraclavicular ± axillary, four synchronous with breast, and five with distant failure. The five-year rate of any nodal recurrence was 1.6% and did not differ by mECE (2.3% vs. 1.3%; p = 0.84). No differences were observed in local (p = 0.08) or distant (p = 0.31) recurrence rates by mECE status. CONCLUSIONS: In Z0011-eligible patients, nodal recurrence rates in patients with mECE are low after treatment with SLN biopsy alone, even in the absence of routine nodal radiation. The presence of mECE should not be considered a routine indication for ALND.

4.
JAMA Netw Open ; 2(11): e1916211, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774522

RESUMO

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. Main Outcomes and Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusions and Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. Trial Registration: ClinicalTrials.gov identifier: NCT02252887.

5.
Nat Med ; 25(10): 1607-1614, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591597

RESUMO

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.


Assuntos
Quimiorradioterapia , Organoides/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Animais , Fluoruracila/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Organoides/efeitos dos fármacos , Organoides/efeitos da radiação , Neoplasias Retais/patologia
6.
Breast Cancer Res Treat ; 178(3): 587-595, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456070

RESUMO

PURPOSE: CIPN is a common, debilitating, and dose-limiting side effect of chemotherapy. Here, we describe characteristics of patients with CIPN using both patient-reported outcomes (PRO) and quantitative sensory testing (QST). METHODS: Breast cancer survivors with persistent moderate to severe CIPN defined by a rating of 4 or greater on a 0-10 Numeric Rating Scale (NRS) from two ongoing clinical trials were included. PROs included the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity (FACT/GOG-Ntx). QST included tactile and vibration detection threshold measurements. Data were analyzed using descriptive statistics and Spearman correlation coefficients. RESULTS: 49 female patients with a mean age of 61 years were assessed; 63% were Caucasian. Mean NRS scores were 4.2, 5.7, and 4.3 on 0-10 scale for pain, numbness, and tingling, respectively. Mean NPS score was 41.0 on a 0-100 scale, and the mean FACT/GOG-Ntx score was 25.8 on a 0-44 scale. QST showed mild to moderate impairments in tactile and vibration perception. The FACT/GOG-Ntx subscale for numbness was negatively correlated with tactile and vibration thresholds in both hands and feet (both p < 0.05). NPS was positively correlated with tactile thresholds in the hands and feet (p < 0.05). CONCLUSION: Patients with moderate to severe CIPN report moderate pain, numbness, and tingling, and exhibit reduced tactile and vibration perception on QST. Weak to moderate correlations were observed between PRO and QST. These data suggest that QST outcomes are associated with CIPN symptoms and may be useful in helping monitor and manage CIPN treatment.

7.
Clin Genitourin Cancer ; 17(4): 268-274.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31151928

RESUMO

BACKGROUND: Mucinous tubular and spindle-cell carcinoma (MTSCC) is a rare kidney cancer subtype with limited cases reported in the literature. We report on outcomes of 25 patients with this variant who were managed at our institution. MATERIALS AND METHODS: The institution database was queried, and clinical data extracted for patients with MTSCC. Molecular features examined included next-generation sequencing with Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets and allele-specific copy number analysis using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm in a subset of patients. RESULTS: All patients underwent primary tumor-directed therapy (nephrectomy = 23, cryoablation = 2). Metastases were diagnosed in 6 patients (24%), 3 (12%) of whom had de novo metastatic disease. Five of 6 patients with metastatic disease had high-grade histological features compared with 0 of 19 nonmetastatic patients (83% vs. 0%; P < .001, Fisher exact test). Three-year overall survival from diagnosis was 84.8% (95% confidence interval, 59.6-94.9) with a median follow-up time of 3.9 years (range, 1 month to 10.3 years). Three deaths occurred, all from metastatic disease. Four patients received systemic therapy with time to treatment failure ≤6 months across different agents with the exception of 1 patient with prolonged response with sunitinib treatment (30.6 months). The most frequent molecular alterations were neurofibromin 2 mutations (n = 2; 40%), germline alterations (n = 2; 40%) including checkpoint kinase 2 and BRCA2 DNA repair associated mutations, multiple chromosomal copy number losses, and mismatch repair deficiency in 1 patient. CONCLUSION: MTSCC is characterized by localized tumors treated successfully with primary tumor-directed therapy. However, patients with high-grade histological features were more likely to develop metastatic disease with limited responses to standard therapies.

8.
J Clin Oncol ; 37(26): 2329-2337, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31233353

RESUMO

PURPOSE: In men with metastatic germ cell tumors (GCTs), risk-directed treatment is determined, in part, by a distinction between seminoma and nonseminomatous GCT (NSGCT). The importance of NSGCT cell type is uncertain. We evaluated the long-term impact of teratoma on survival in patients with NSGCT. METHODS: Prechemotherapy, primary tumors from patients who received platinum-based chemotherapy were studied, and the histology was confirmed by a genitourinary pathologist. The cumulative incidence of disease-related death (CIDD) was the primary end point, and a competing-risk analysis was performed. RESULTS: Tumors were available from 232 patients, including 193 with NSGCT. An element of teratoma was present in 82 NSGCT primary tumors (42%). With a median follow-up of 17 years (range, 0.3 to 35 years), 58 patients with NSGCT died, 47 as a result of GCT and 11 as a result of other causes. Most GCT deaths occurred within the first 5 years and were associated with pretreatment risk status (P < .001). Death as a result of other causes rose steadily after 15 years and was not associated with risk status (P = .66). A higher CIDD was observed in patients who had NSGCT with teratoma than those with NSGCT without teratoma and seminoma (5-year CIDD rate, 27.4%, 17.4%, and 10.3%, respectively; P = .03). A higher CIDD was observed in patients who had NSGCT with mature teratoma compared with those with either NSGCT with immature teratoma or NSGCT without teratoma (5-year CIDD rate, 38.1%, 19.9%, and 17.4%, respectively; P = .01). CONCLUSION: The presence of teratoma, particularly mature teratoma, in an NSGCT primary tumor is associated with a higher CIDD, consistent with the hypothesis that differentiation is associated with adverse outcomes. Death as a result of non-GCT causes is not associated with risk status and must be separated from GCT death when evaluating long-term survival.

9.
Clin Genitourin Cancer ; 17(3): e678-e688, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31036466

RESUMO

BACKGROUND: Sarcomatoid features (SF) in renal cell carcinoma (RCC) denote poor prognosis. Data for metastatic chromophobe RCC (ChRCC) with SF are limited. We studied clinical outcomes and genomic features in this setting. PATIENTS AND METHODS: We performed a retrospective review of newly diagnosed metastatic ChRCC patients; end points included overall survival (OS), time to treatment failure (TTF), and time to metastatic recurrence (TTR) after nephrectomy for localized disease. A subset of patients underwent next-generation sequencing (NGS). Outcomes were compared using nonparametric tests. RESULTS: One hundred nine patients with metastatic ChRCC were identified including 29 with SF. Median TTR after nephrectomy was shorter for patients with versus without SF (2.7 months [95% confidence interval (CI), 0.7-6.9] versus 48.8 months [95% CI, 30.8-80.7], log rank P < .001). Median TTF during first-line therapy was shorter for patients with versus without SF (1.8 months [95% CI, 0.9-2.7] vs. 8.0 months [95% CI, 5.1-13.0]; log rank P < .001). No responses were observed in 6 patients treated with nivolumab including 4 with SF. Median OS was inferior for patients with versus without SF (38 months vs.7.5 months; hazard ratio, 4.7 [95% CI, 2.7-8.2]; P < .001). NGS, performed in 22 patients, showed that 64% and 45% harbored tumor protein P53 and phosphatase and tensin homolog alterations, respectively. Microsatellite instability high status was identified in 3 patients. CONCLUSION: Metastatic ChRCC patients with SF had worse outcomes compared with those without SF. Median TTR < 3 months for this subgroup supports close surveillance after nephrectomy for localized tumors. Lack of benefit with various systemic regimens warrants studying underlying biology and investigating novel agents.

10.
Breast Cancer Res Treat ; 177(1): 61-66, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144151

RESUMO

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are known to have significant clinical and pathological response to neoadjuvant systemic therapy (NST). The aim of this study was to identify factors associated with pathological complete response (pCR), defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is ypN0), among patients with HER2-positive breast cancer and to compare pCR rates between breast cancers with HER2 protein overexpression by immunohistochemistry (IHC) versus HER2 gene amplification by fluorescence in situ hybridization (FISH) in the absence of protein overexpression by IHC. METHODS: We conducted a retrospective review of HER2-positive breast cancer patients treated with NST and surgery at Memorial Sloan Kettering Cancer Center between January 2013 and May 2018. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were assessed according to the 2018 ASCO/CAP guidelines. RESULTS: During the study period, 560 patients were identified. Of 531 patients with IHC results available, 455 patients had HER2 IHC 3+, and 76 had IHC < 3+ but HER2 amplification detected by FISH. The overall pCR rate was 59% (330/560). The pCR rate among patients with HER2 protein overexpression (IHC 3+) was 67%, compared to 17% among patients with HER2 amplification by FISH (IHC < 3+). On univariate and multivariate analyses, HER2 protein overexpression by IHC (IHC 3+) was a significant predictor of pCR, along with grade 3 histology, PR-negative status, and dual anti-HER2 therapy. CONCLUSION: Although both HER2 IHC and FISH are standard HER2 testing methods in breast cancer, achievement of pCR is associated with HER2 IHC expression level, among other factors.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Receptor ErbB-2/genética , Adulto , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
11.
Clin Cancer Res ; 25(13): 3784-3792, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30988080

RESUMO

PURPOSE: Lapatinib and capecitabine cross the blood-tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS). We derived a rational drug scheduling of intermittent high-dose lapatinib alternating with capecitabine based on our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis. PATIENTS AND METHODS: We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2+) breast cancer with CNS metastasis. Lapatinib was given on day 1-3 and day 15-17 with capecitabine on day 8-14 and day 22-28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1,500 mg BID. Toxicity and efficacy were evaluated. RESULTS: Eleven patients were enrolled: brain only (4 patients, 36%), leptomeningeal (5 patients, 45%), and intramedullary spinal cord (2 patients, 18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The MTD of lapatinib was 1,500 mg BID. Three patients remained on therapy for greater than 6 months. CONCLUSIONS: High-dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in patients with HER2+ breast cancer with CNS metastasis and warrants further investigation.

12.
Prep Biochem Biotechnol ; 49(4): 407-418, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30821198

RESUMO

Curcuminoids, the active components of dried rhizome of Curcuma longa have been extracted using batch extraction and three-phase partitioning (TPP) process. The effect of different processing parameters, namely different solvents, extraction time, ammonium sulfate concentration, slurry to tert-butanol ratio, and solute to aqueous ratio on extraction efficiency of TPP, was studied to attain maximum extraction yield. The highest yield of 58.38 mg/g was achieved at 40±2 °C in 150 min, with saturated ammonium sulfate 30% (w/v), slurry to tert-butanol ratio 1:1 (v/v), and turmeric powder to water ratio 1:40 (w/v) in TPP. However, batch extraction using ethanol as a solvent yielded 52.77 mg/g in 180 min extraction time at 40±2 °C with 1:40 (w/v) turmeric powder to water ratio and 400 rpm agitation speed. In view of reference method, i.e., Soxhlet extraction (100%), TPP showed 65.63% yield in 150 min and batch exhibited 59.92% in 180 min. The turmeric extracts obtained by different methods exhibited excellent antioxidant and anti-inflammatory activities equivalent to their respective reference standards. Hence, TPP extraction process assures a rapid and improved recovery of curcuminoids with excellent therapeutic properties.


Assuntos
Antioxidantes/isolamento & purificação , Curcuma/química , Curcumina/isolamento & purificação , Extração em Fase Sólida/métodos , Álcoois/química , Sulfato de Amônio/química , Anti-Inflamatórios , Antioxidantes/análise , Curcumina/análise , Rizoma/química , Solventes/química , Temperatura Ambiente
13.
PLoS One ; 14(2): e0210891, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763338

RESUMO

BACKGROUND: This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored. PATIENTS AND OUTCOME MEASURES: Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses. RESULTS: The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones. CONCLUSIONS: This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT01830244.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia Neoadjuvante , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Nanopartículas/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Albumina Sérica Humana/administração & dosagem , Albumina Sérica Humana/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
14.
J Gastrointest Surg ; 23(4): 794-799, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30719677

RESUMO

BACKGROUND: Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates. METHODS: We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort. RESULTS: From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate. CONCLUSIONS: Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

15.
Oncologist ; 24(8): e646-e652, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30602614

RESUMO

BACKGROUND: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. MATERIALS AND METHODS: In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. RESULTS: From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. CONCLUSION: With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. IMPLICATIONS FOR PRACTICE: The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

16.
J Gastrointest Surg ; 23(4): 800-807, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30350191

RESUMO

BACKGROUND: Neoadjuvant chemoradiation (CRT) impairs bowel function in patients with rectal cancer treated with total mesorectal excision (TME). The impact of other forms of neoadjuvant therapy such as neoadjuvant chemotherapy alone (NC) and induction chemotherapy followed by CRT (total neoadjuvant therapy or TNT) on postoperative bowel function has not been investigated. METHODS: We conducted a retrospective review of 176 rectal cancer patients treated between November 1, 2011, and August 31, 2017. All patients completed the MSKCC Bowel Function Instrument (BFI), a validated bowel function questionnaire, at least 6 months after TME and/or ileostomy reversal. Differences in BFI scores were compared across four groups (surgery alone, CRT, NC, and TNT) and also according to exposure to neoadjuvant RT and neoadjuvant chemotherapy. A multivariable linear regression model was used to evaluate the independent relationship between exposure to neoadjuvant RT or chemotherapy and BFI. RESULTS: BFI total scores were significantly different between the four groups (p = 0.008). Exposure to RT correlated with worse BFI total scores (p = 0.002), and no differences were found in BFI total score after exposure to neoadjuvant chemotherapy (p = 0.92). In a linear regression model, only exposure to RT (ß = - 5.1; 95% CI - 8.9 to - 1.3; p = 0.008) and tumor distance from the anal verge (ß = 1.23; 95% CI 0.48 to 1.97; p = 0.001) were significantly correlated with BFI total score. CONCLUSION: NC, whether administered alone or added to CRT, does not seem to impair bowel function. These data should be used to counsel rectal cancer patients when discussing neoadjuvant therapy options.

17.
Dis Colon Rectum ; 61(10): 1146-1155, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30192323

RESUMO

BACKGROUND: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response. OBJECTIVE: The purpose of this study was to analyze disease-free and overall survival. DESIGN: This was a nonrandomized phase II trial. SETTINGS: The study was conducted at multiple institutions. PATIENTS: Four sequential study groups with stage II or III rectal cancer were included. INTERVENTION: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6. MAIN OUTCOME MEASURES: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study. RESULTS: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03). LIMITATIONS: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients. CONCLUSIONS: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Reto/patologia , Idoso , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados não Aleatórios como Assunto/métodos , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Neoplasias Retais/cirurgia , Reto/cirurgia , Resultado do Tratamento
18.
Breast Cancer Res Treat ; 172(2): 247-263, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30094552

RESUMO

PURPOSE: We conducted a systematic review and meta-analysis to measure the extent to which race is associated with delayed initiation or receipt of inadequate chemotherapy among women with early-stage breast cancer. METHODS: We performed a systematic search of all articles published from January 1987 until June 2017 within four databases: PubMed/Medline, EMBASE, CINAHL, and Cochrane CENTRAL. Eligible studies were US-based and examined the influence of race on chemotherapy delays, cessation, or dose reductions among women with stage I, II, or III breast cancer. Data were pooled using a random effects model. RESULTS: A total of twelve studies were included in the quantitative analysis. Blacks were significantly more likely than whites to have delays to initiation of adjuvant therapy of 90 days or more (OR 1.41, 95% CI 1.06-1.87; X² = 31.05, p < 0.00001; I² = 90%). There was no significant association between race and chemotherapy dosing. Due to overlap between studies assessing the relationship between race and completion of chemotherapy, we conducted two separate analyses. Black patients were significantly more likely to discontinue chemotherapy, however, this was no longer statistically significant when larger numbers of patients with more advanced (stage III) breast cancer were included. CONCLUSIONS: These results suggest that black breast cancer patients experience clinically relevant delays in the initiation of adjuvant chemotherapy more often than white patients, which may in part explain the increased mortality observed among black patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Afro-Americanos , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Grupos de Populações Continentais , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Estadiamento de Neoplasias
19.
JAMA Oncol ; 4(9): 1228-1235, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29978187

RESUMO

Importance: Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives: To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants: In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures: Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results: Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non-clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance: Of patients with non-clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.


Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/diagnóstico , Estudos de Coortes , Feminino , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Humanos , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
20.
Clin Breast Cancer ; 18(5): 387-394, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29680193

RESUMO

BACKGROUND: Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial. PATIENTS AND METHODS: Patients had received ≤ 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit. RESULTS: From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL. CONCLUSION: This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Dasatinibe/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Dasatinibe/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Intervalo Livre de Progressão , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA